Myogenic vasoconstriction requires canonical Gq/11 signaling of the angiotensin II type 1a receptor in the murine vasculature
Autor/innen
- Y. Cui
- M. Kassmann
- S. Nickel
- C. Zhang
- N. Alenina
- Y.M. Anistan
- J. Schleifenbaum
- M. Bader
- D.G. Welsh
- Y. Huang
- M. Gollasch
Journal
- bioRxiv
Quellenangabe
- bioRxiv
Zusammenfassung
BACKGROUND: The myogenic response is an inherent vasoconstrictive property of resistance arteries to keep blood flow constant in response to increases in intravascular pressure. Angiotensin II (Ang II) type 1 receptors (AT1R) are broadly distributed, mechanoactivated receptors, which have been proposed to transduce myogenic vasoconstriction. However, the AT1R subtype(s) involved and their downstream G protein- and β-arrestin-mediated signaling pathways are still elusive. OBJECTIVE: To characterize the function of AT1aR and AT1bR in the regulation of the myogenic response of resistance size arteries and possible downstream signaling cascades mediated by G(q/11) and/or β-arrestins. METHODS: We used Agtr1a(-/-), Agtr1b(-/-) and tamoxifen-inducible smooth muscle-specific AT1aR knockout mice (SM-Agtr1a mice). FR900359, [Sar1, Ile4, Ile8] Ang II (SII) and TRV120055 were used as selective G(q/11) protein inhibitor and biased agonists to activate non-canonical β-arrestin and canonical G(q/11) signaling of the AT1R, respectively. RESULTS: Myogenic and Ang II-induced vasoconstrictions were diminished in the perfused renal vasculature of Agtr1a(-/-) and SM-Agtr1a mice. Similar results were observed in isolated pressurized mesenteric and cerebral arteries. Myogenic tone and Ang II-induced vasoconstrictions were normal in arteries from Agtr1b(-/-) mice. The G(q/11) blocker FR900359 decreased myogenic tone and Ang II vasoconstrictions while selective biased targeting of AT1R β-arrestin signaling pathways had no effects. CONCLUSION: The present study demonstrates that myogenic arterial constriction requires G(q/11)-dependent signaling pathways of mechanoactivated AT1aR but not G protein-independent, noncanonical alternative signaling pathways in the murine mesenteric, cerebral and renal circulation.